Cancers are now recognized as being driven by widespread changes in the epigenome including changes in DNA methylation and chromatin packaging. Changes in DNA methylation include global loss of methylation and focal gain of methylation at promoter regions of tumor suppressor genes leading to transcriptional silencing. DNA methylation, the covalent modification of DNA, is mediated by a family of DNA methyltransferases (DNMTs). In recent years, inhibitors of DNMTs (DNMTis) have emerged as therapeutic targets for treatment of myeloid malignancies as well as cutaneous T cell lymphoma. In 2004, the FDA approved the DNMT inhibitor 5-azacitidine (AZA) for treatment of myelodysplastic syndrome. Several groups, including the present inventors, have focused on the therapeutic potential of DNMT inhibitors in the treatment of solid tumors with exciting early possibilities seen in non-small cell lung cancer (NSCLC) and to reverse chemotherapy resistance in ovarian cancers. Recently, in a small number of patients, the present inventors have also seen exciting robust clinical responses in patients with NSCLC who happened to have received therapy to break immune tolerance after having received epigenetic therapy with a DNMTi, 5-azacitidine (AZA), along with an HDAC inhibitor (HDAC), Entinostat.